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HUMAN GENETIC VARIATION REGULATING SALMONELLA HOST-PATHOGEN INTERACTIONS AND DISEASE SUSCEPTIBILITY

调节沙门氏菌宿主-病原体相互作用和疾病易感性的人类遗传变异

基本信息

批准号：
10621956
负责人：
Dennis Chun-Yone Ko
金额：
$ 45.36万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621956
关键词：
Affect Alleles B lymphocyte immortalization Bacteremia Cell membrane Cells Cessation of life Cholesterol Clinical Communicable Diseases Cultured Cells Data Data Set Disease Disease susceptibility Dissection Divalent Cations Docking Enteral Enterocytes Epithelial Cells Functional disorder Funding Gastroenteritis Gene Expression Genes Genetic Genetic Variation Genome Genotype Goals Guanosine Triphosphate Phosphohydrolases Heterozygote Histopathology Human Human Genetics Immune Immune response In Vitro Inbred Strains Mice Individual Infection Inflammation Invaded Knockout Mice Macrophage Measures Mediating Membrane Modeling Molecular Morbidity - disease rate Multi-Drug Resistance Mus Mutation Nutrient Oral Outcome Patients Phenotype Plasma Play Population Predisposition Production Regulation Resolution Resources Risk Role Salmonella Salmonella infections Salmonella typhimurium Signal Pathway System Systemic disease Testing Therapeutic Intervention Type III Secretion System Pathway Typhoid Fever Validation Variant Whole Organism cytokine gastrointestinal epithelium genetic makeup genetic variant genome wide association study human disease human population study improved induced pluripotent stem cell infected B cell lymphoblastoid cell line metal poisoning monocyte mortality mouse model non-typhoidal Salmonella novel novel therapeutic intervention oral infection pathogen polarized cell rho screening trait

项目摘要

Salmonellae cause an estimated 150 million cases of gastroenteritis and 25 million cases of invasive disease (enteric fever and non-typhoidal bacteremia), leading to 300,000 deaths per year. Findings based on inbred mouse strains and rare human mutations indicate that the clinical presentations and outcomes of salmonellosis are influenced by the host’s genetic makeup. However, we do not understand the impact of common, naturally occurring human genetic differences on Salmonella infections. Our long-term goal is to leverage high- throughput cellular phenotyping of infection and natural genetic diversity to define molecular parameters of susceptibility to human infectious diseases. While genome-wide association studies (GWAS) of enteric fever and bacteremia identified genetic differences regulating susceptibility, such studies are limited by high variability in patient exposure, pathogen genetic diversity, and a limited understanding of the pathophysiology of identified variants. We developed a complementary cellular GWAS approach (Hi-HOST: High-throughput Human in vitrO Susceptibility Testing; http://h2p2.oit.duke.edu) to perform high resolution analysis of human genetic differences that impact host-pathogen traits while enabling experimental dissection of these traits. In the previous funding period, we focused on human genetic variants that regulate Salmonella invasion of host cells. We identified a regulatory variant in VAC14 that modulates levels of plasma membrane cholesterol and thus limits the docking of the Salmonella SPI-1 type III secretion system to host cells. Humans with the high-invasion allele of VAC14 have increased risk of typhoid fever and bacteremia. The objectives of this application are to define and characterize human genetic differences that alter the full spectrum of Salmonella host-pathogen interactions and assess their impact on disease. Building from our unique resource of Hi-HOST cellular GWAS of Salmonella invasion, replication, and host cytokine levels, we have identified SNPs mediating susceptibility to infection phenotypes that will undergo experimental validation and mechanistic studies. We will determine how regulatory SNPs affecting ARHGEF26 and MCOLN2 expression impact Salmonella invasion and replication and the role these genes play during infection in mice. For ARHGEF26, a Rho GEF that stimulates Salmonella-induced membrane ruffling, our association data and experimental evidence indicate SNPs regulate ARHGEF26 expression to increase invasion dependent on the Salmonella effector sopB. For MCOLN2, we hypothesize that this divalent cation channel is a novel factor that regulates intracellular replication by modulating nutrient access, metal toxicity, and/or immune cell polarization. Using Arhgef26 and Mcoln2 mice, we will elucidate how altered expression of these genes regulates bacterial burden and immune response during infection. Finally, we will test whether SNPs identified by Hi-HOST are associated with enteric fever and bacteremia in humans. Revealing these mechanisms could lead to new therapeutic strategies for salmonellosis and other diseases impacted by the same genetic variants.

沙门氏菌引起估计1.5亿例胃肠炎和2500万例侵袭性疾病（肠热病和非伤寒菌血症），每年导致30万人死亡。基于近亲繁殖的结果小鼠品系和罕见的人类突变表明沙门氏菌病的临床表现和结果都受到宿主基因构成的影响但是，我们不了解共同的影响，自然人类对沙门氏菌感染的遗传差异。我们的长期目标是利用高- 通过感染和自然遗传多样性的细胞表型分析来确定易感染人类传染病。虽然全基因组关联研究（GWAS）的肠热病和菌血症确定了调节易感性的遗传差异，这类研究受到以下因素的高度变异性的限制：患者暴露，病原体遗传多样性，以及对已确定的变体。我们开发了一种互补的细胞GWAS方法（Hi-HOST：高通量人体外培养）。易感性测试; http://h2p2.oit.duke.edu）来进行人类遗传差异的高分辨率分析影响宿主-病原体特征，同时使这些特征的实验解剖成为可能。在此前的融资中，在此期间，我们专注于调节沙门氏菌入侵宿主细胞的人类遗传变异。我们确定了一个 VAC 14中的调节变体，其调节质膜胆固醇水平并因此限制对接的沙门氏菌SPI-1 III型分泌系统的宿主细胞。具有VAC 14高侵袭等位基因的人类会增加患伤寒和菌血症的风险。本申请的目的是定义和表征改变沙门氏菌宿主-病原体全谱的人类遗传差异并评估其对疾病的影响。利用我们独特的沙门氏菌入侵、复制和宿主的Hi-HOST细胞GWAS资源构建在细胞因子水平上，我们已经确定了介导感染表型易感性的SNP，这些表型将经历实验验证和机理研究。我们将确定调控SNP如何影响ARHGEF 26 和MCOLN 2的表达影响沙门氏菌的入侵和复制，以及这些基因在沙门氏菌入侵和复制过程中所起的作用。感染小鼠。对于ARHGEF 26，一种刺激沙门氏菌诱导的膜皱褶的Rho GEF，我们的相关数据和实验证据表明，SNPs调节ARHGEF 26的表达，以增加侵袭依赖于沙门氏菌效应子sopB。对于MCOLN 2，我们假设这种二价阳离子通道是一种通过调节营养获取、金属毒性和/或免疫调节细胞内复制的新因子细胞极化使用Arhgef 26和Mcoln 2小鼠，我们将阐明这些基因的表达改变是如何发生的。在感染期间调节细菌负荷和免疫应答。最后，我们将测试是否SNPs识别与人类的肠热病和菌血症有关。揭示这些机制可以为沙门氏菌病和其他受相同遗传变异影响的疾病带来新的治疗策略。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Methylthioadenosine Suppresses Salmonella Virulence.

DOI：
10.1128/iai.00429-18
发表时间：
2018-09
期刊：
Infection and immunity
影响因子：
3.1
作者：
Bourgeois JS;Zhou D;Thurston TLM;Gilchrist JJ;Ko DC
通讯作者：
Ko DC

Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation.

DOI：
10.1016/j.xgen.2023.100290
发表时间：
2023-05-10
期刊：
CELL GENOMICS
影响因子：
0
作者：
Gibbs, Kyle D.;Wang, Liuyang;Yang, Zhuo;Anderson, Caroline E.;Bourgeois, Jeffrey S.;Cao, Yanlu;Gaggioli, Margaret R.;Biel, Martin;Puertollano, Rosa;Chen, Cheng-Chang;Ko, Dennis C.
通讯作者：
Ko, Dennis C.

These Are the Genes You're Looking For: Finding Host Resistance Genes.